NM_004004.6(GJB2):c.269T>C (p.Leu90Pro) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (15 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000018541.63

Allele description [Variation Report for NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)]

NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)

HGVS:

NC_000013.11:g.20189313A>G
NG_008358.1:g.8663T>C
NM_004004.6:c.269T>CMANE SELECT
NP_003995.2:p.Leu90Pro
NP_003995.2:p.Leu90Pro
LRG_1350t1:c.269T>C
LRG_1350:g.8663T>C
LRG_1350p1:p.Leu90Pro
NC_000013.10:g.20763452A>G
NM_004004.5:c.269T>C
P29033:p.Leu90Pro
c.269T>C
c.269T>C (p.Leu90Pro)
p.LEU90PRO

Protein change:

L90P; LEU90PRO

Links:

UniProtKB: P29033#VAR_015937; OMIM: 121011.0016; dbSNP: rs80338945

NCBI 1000 Genomes Browser:

rs80338945

Molecular consequence:

NM_004004.6:c.269T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038823	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000041043	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (3) [See all records that cite these PMIDs] 11313763, 16380907, 20301449
SCV000492908	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2013)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000538033	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000599742	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (May 9, 2017)	germline	clinical testing	Citation Link,
SCV000863417	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 11, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919425	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 1, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11493200, 10982180, 12189487, 24793888, 17041943, 12189493 Citation Link,
SCV001193908	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 7, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12505163, 10830906, 12189493, 12189487, 15967879, 21094084 Citation Link,
SCV001453341	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001523117	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 19, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002577328	Wangler Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	maternal	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10218527, 12189487, 12497637, 15365987, 12189493, 16300957, 25741868
SCV003935286	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175950	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051793	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	2	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	14	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Native American	unknown	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sensorineural hearing loss and the incidence of Cx26 mutations in Austria.

Löffler J, Nekahm D, Hirst-Stadlmann A, Günther B, Menzel HJ, Utermann G, Janecke AR.

Eur J Hum Genet. 2001 Mar;9(3):226-30.

PubMed [citation]

PMID:: 11313763

GJB2 mutations and degree of hearing loss: a multicenter study.

Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, et al.

Am J Hum Genet. 2005 Dec;77(6):945-57. Epub 2005 Oct 19.

PubMed [citation]

PMID:: 16380907
PMCID:: PMC1285178

See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000038823.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Loffler et al. (2001) detected a leu90-to-pro (L90P) substitution in the GJB2 gene in 5 of 26 (19.2%) GJB2 alleles in 13 unrelated Austrian patients with autosomal recessive neurosensory hearing loss (220290). GJB2 mutations were detected on both alleles. The onset of hearing loss in compound heterozygous individuals was prelingual in 2 cases, perilingual in 1 case, and in the first decade in 2 cases. See also (121011.0017).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000041043.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV000492908.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538033.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.269T>C (p.Leu90Pro) missense variant in the GJB2 gene is a common variant reported in individuals affected with autosomal recessive nonsyndromic hearing loss and deafness (LÃ¶ffler et al., 2001). This variant has been observed in trans with the well-characterized GJB2c.35delG variant (Denoyelle et al., 1999, LÃ¶ffler et al., 2001). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (ThÃ¶nnissen et al., 2002; D'Andrea et al., 2002; Bruzzone et al., 2003; Palmada et al., 2006). This c.269T>C has been reported at low frequency or absent in three control population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA, and ExAC = 0.151%). Multiple lines of computational evidence predict a deleterious effect (GERP = 5.33; CADD = 23.5; PolyPhen = 1; SIFT = 0), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.269T>C (p.Leu90Pro) as a recessive pathogenic variant for Nonsyndromic hearing loss and deafness.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000599742.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	not provided
2	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		14	not provided	not provided	not provided
2	germline	no	not provided	not provided	not provided		2	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH, SCV000863417.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Native American	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	blood	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919425.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: The GJB2 c.269T>C (p.Leu90Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, and this mutation affects a highly conserved residue of the encoded gap junction protein and has been shown to be coupling deficient by in vitro functional assays (Thonnissen_2001). The observed allele frequency in controls, including the large and diverse ExAC cohort, is 108/123096 (1/1140), which is lower than the maximal expected allele frequency for an ARNSHL-causing GJB2 variant (1/40). This variant has been reported in several NSHL patients in homozygous as well as compound heterozygous state with other pathogenic variants, including evidence of cosegregation with disease in multiple families (Rabionet_2000, Marlin_2001, Tang_2006, Salvago_2014). In addition, several diagnostic laboratories/reputable databases classify the variant as pathogenic. Taking all evidence together, this variant has been classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193908.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

NM_004004.5(GJB2):c.269T>C(L90P) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 12505163, 10830906, 12189493, 12189487, 15967879, and 21094084. Classification of NM_004004.5(GJB2):c.269T>C(L90P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453341.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001523117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Wangler Lab, Baylor College of Medicine, SCV002577328.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (7)

Description

This missense GJB2 variant at c.269T>C (p.L90P) was discovered on exome through the Texome Project (R01HG011795). It has been reported in individuals with non-syndromic hearing loss 1A (PMID: 10218527, 12189487, 12497637, 15365987) (PM3), and functional studies suggest this variant is partially defective (PMID: 12189493, 16300957) (PS3). It has been observed in gnomAD with a frequency of 0.060% in the heterozygous state (PM2). This variant is predicted to be deleterious by multiple computational models (CADD: 28.800)(PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Integrating Genomics into Medicine, Frazer Institute, University Of Queensland, SCV003935286.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004175950.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PM3_VSTR,PM5_STR,PS3_SUP,PP3; origin unknown but compound heterozygous

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004808263.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051793.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004808263	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004808263

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 29, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Nov 3, 2024

Relating variation to medicine